Written by: Domhnall Mc Gowan M.Sc.
Classification of laboratory and cleanroom spaces can be divided in to two main categories. Category 1 is classified based on air cleanliness, and category 2 is based on biosafety or containment requirements. The distinguishing feature on what type of classification you should be considering is based on the activity that will be carried out in the space. In this article we will be talking about classification of cleanrooms based on air cleanliness, or quantification of airborne particles.
Cleanrooms are primarily classified by the quality of the air, which means that the air quality must meet certain criteria for particle quantity and size per cubic meter (m3) or cubic foot (ft3) of air sampled. Cleanrooms are used to manufacture sensitive medical and electronic products. Small particles can severly impact the quality of these products. Electronics such as semiconductors can malfunction if introduction of small particles occurs during production, and terminally sterilized or aseptically produced medical products such as drugs and stem cell therapies can illicit severe reactions if particles adulterate them.
Defining Classifications
There are many governing or regulatory bodies which lay out requirements for production of sensitive products depending on the product type and geographical location of the manufacturing facility.
ISO-14644
When it comes to classification of airborne particles the International Organization for Standardization publishes guidelines which are adopted and incorporated by all the major global regulatory bodies. Specifically for cleanroom classification based off quantification of airborne particulates they publish ISO-14644-1: Classification of air cleanliness by particle concentration. This guideline lays out the cleanroom classification categories and the specifications for each category in terms of particle size and quantity. Those categories are:
Maximum allowable concentrations (particles/m3) of particles equal to and greater than the considered size | ||||||
| ISO Class | 0.1µm | 0.2µm | 0.3µm | 0.5µm | 1.0µm | 5.0µm |
| ISO1 | 10 | - | - | - | - | - |
| ISO2 | 100 | 24 | 10 | - | - | - |
| ISO3 | 1 000 | 237 | 102 | 35 | - | - |
| ISO4 | 10 000 | 2 370 | 1 020 | 352 | 83 | - |
| ISO5 | 100 000 | 23 700 | 10 200 | 3 520 | 832 | - |
| ISO6 | 1 000 000 | 237 000 | 102 000 | 35 200 | 8 320 | 293 |
| ISO7 | - | - | - | 352 000 | 83 200 | 2930 |
| ISO8 | - | - | - | 3 520 000 | 832 000 | 29 300 |
| ISO9 | - | - | - | 35 200 000 | 8 320 000 | 293 000 |
Table 1: ISO-4644-1 cleanroom classifications
US Food and Drug Administration (FDA)
The US FDA, and associated federal bodies, publish the Code of Federal Regulations (CFR). 21 CFR Part 211 specifies the requirements for producing drug products and alongside the Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing document they lay out the cleanroom classification requirements that need to be met when manufacturing drug products. In their guidance they make some modifications:
i) Focus on ISO designations 5-8.
ii) Assign equivalent Clean Area Classifications (particles/ft3)
iii) Focus on 0.5µm particle sizes
iv) Include microbiological air specifications
See Table 2 and 3 for further information.
European Union (EU)
The EU and its related governing bodies publish their own directives which lay out the requirements for classification of cleanrooms. Similar to the FDA they incorporate and expand on ISO-14644-1. EudraLex Volume 4 Annex 1: Manufacture of Sterile Medicinal Products outlines the classification requirements for cleanrooms producing medicinal products. In this guidance they categorize areas as follows:
i) Areas are classified as Grade A, B, C, or D
ii) Specify particle requirements for 0.5 µm and 5.0 µm particle sizes
iii) Provide specification for “at rest” and “in operation” states.
iv) Provide microbiological limits for specified grades
See Table 2 and 3 for further information.
Other Governing Bodies
The FDA and EU are two of the main governing bodies however many countries will have their own, and there are also other international bodies which provide regulatory guidelines on the classification of cleanrooms. These other bodies generally follow the lead of either the FDA or EU, or just wholly incorporate ISO-14644-1.
| Maximum allowable concentrations of particles | FDA (particles/ ft3) | EU (particles/ m3) | ||||
| Class | 0.5µm (ft3) | 0.5 µm (m3) | 5.0 µm (m3) | Class | At rest | In operation |
| ISO5 | 100 | 3 520 | - | 100 | Grade A Grade B | Grade A |
| ISO6 | 1 000 | 35 200 | 293 | 1 000 | ||
| ISO7 | 10 000 | 352 000 | 2930 | 10 000 | Grade C | Grade B |
| ISO8 | 100 000 | 3 520 000 | 29 300 | 100 000 | Grade D | Grade C |
Table 2: Comparison of ISO -14644-1, FDA cGMP and EU GMP specifications for cleanroom classifications based on particle quantification criteria. Modified from ISO-14644-1, EudraLex Volume 4 Annex 1: Manufacture of Sterile Medicinal Products, and FDA Guidance for Industry: Sterile Drug Product Produced by Aseptic Processing.
| ISO Class | FDA | EU GMP | Grade | |||
|---|---|---|---|---|---|---|
| Air sample (cfu/m3) | Settle plate (cfu/4hours) | Air sample (cfu/m3) | Settle plate (cfu/4hours) | Contact plate (cfu/plate) | ||
| ISO5 | 1 | 1 | No growth | No growth | No growth | A |
| ISO6 | 7 | 3 | ||||
| ISO7 | 10 | 5 | 10 | 5 | 5 | B |
| ISO8 | 100 | 50 | 100 | 50 | 25 | C |
| ISO9 | 200 | 100 | 50 | D | ||
Table 3: Comparison of microbiological limits set by FDA cGMP and EU GMP for equivalent clean spaces. Modified from EudraLex Volume 4 Annex 1: Manufacture of Sterile Medicinal Products and FDA Guidance for Industry: Sterile Drug Product Produced by Aseptic Processing.
Validation and Maintenance of Cleanrooms Classifications
To truly state that a cleanroom meets the above classifications it must be validated against the specifications set out by the regulatory body. This is an initial process of data gathering over a set period of time and then an ongoing process where air quality is routinely monitored for particles. Specialized equipment and technical documentation are needed to carry out this validation process. Additionally, time must be spent maintaining the systems and components which ensure the air quality continues to meet the specifications.
How Vibraclean can help
Vibraclean are experts in facility monitoring and maintenance. We can be your partners in developing your cleanroom validation and maintenance plan. Vibraclean also act as sterility maintenance providers and can provide guidance on SOP development and training of your facility personnel.